There hasn’t been much good news for patients with the prevalent but enigmatic disorder chronic fatigue syndrome (also referred to as myalgic encephalomyelitis). Over decades, research into the pathophysiology has failed to find convincing evidence of either persistent infection or immunological, endocrine, or metabolic change, and has rejected simplistic notions of depression (typical or atypical) or primary sleep disorder. Several notable “breakthroughs” have failed independent replication. The most noteworthy is the recent rise and fall of xenotropic murine leukaemia virus related virus
(XMRV) as the cause, which was ultimately established as a murine DNA laboratory contaminant.1 Similarly, an exhaustive array of randomised controlled trials seeking curative outcomes from antiviral, immunological, hormonal, antidepressant, and many other therapies havefailed to show any benefit over placebo, or failed the replication test.

Where then is the progress? Firstly, there is reproducible evidence
implicating certain infections as a trigger—notably, infectious
mononucleosis caused by Epstein-Barr virus, but also infection with other pathogens.2 Secondly, there is clear evidence that a substantial proportion of patients have a coexisting mood disorder, and sometimes a sleep-wake disorder, and that these conditions may exacerbate or perpetuate the illness.3 Thirdly, independent studies using both structural and functional imaging techniques have identifiedalterations in the brains of patients with chronic fatigue syndrome, implicating the central nervous system as the site of pathophysiology.4 Fourthly, there is solid evidence from multiple controlled studies that patients can gain control of symptoms and functional improvement through multidisciplinary interventions incorporating graded exercise therapy and cognitive behavioural therapy. These interventions have clearly positive outcomes in systematic reviews and meta-analyses.5 6 7 For instance, the recent Cochrane review of graded exercise therapy5 states that “patients with CFS [chronic fatigue syndrome] may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that
exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed.”

How therapy works

Plausibly, graded exercise may reverse a perpetuator in the form of physical deconditioning. However, there is little evidence for loss of aerobic fitness in patients with chronic fatigue syndrome, and limited evidence for improved physical performance after successful graded exercise therapy.8 Instead, graded exercise has been proposed to act by desensitising an exaggerated central nervous system response to the physiological signals associated with exercise.9 In psychological terms, patients may avoid activity because of the prolonged exacerbation of symptoms that follows minor physical activity; this leads to an understandable conclusion that exercise is harmful or to a
conditioned fear of such activity.10 In this respect, the recent
mediation analysis of the outcomes of the PACE trial is of interest.11 This trial compared standard medical care, cognitive behavioural therapy, graded exercise, and adaptive pacing therapy, concluding that both cognitive behavioural and graded exercise therapy were more effective at reducing fatigue and improving physical disability than standard care or adaptive pacing.12 The mediation analysis suggested that both cognitive behavioural therapy and graded exercise worked by
reducing avoidance of activity. This is broadly consistent with
findings by others,13 although whether the effect simply relates to
the behavioural change itself (that is, exercise) or reconditioning of the associated fear of activity remains unclear. In addition, a
substantial proportion of patients do not avoid activity but have
repeated boom-bust cycles of overactivity when feeling relatively well (the boom) followed by reduced activity when symptoms are exacerbated thereafter (the bust). These data argue for a personalised approach to both therapies.

Cognitive behavioural therapy for patients with chronic fatigue
syndrome is based on the premise that inappropriate cognitive
attributions (thinking patterns) and behaviours help perpetuate
symptoms. It seeks to alter these attributions and modify the
associated behaviour, targeting activity patterns and sleep-wake
behaviours. For example, although primary sleep disorders do not
explain chronic fatigue syndrome,14 patients typically report that
their night-time sleep is unrefreshing, and as fatigue is the dominant symptom, patients may consider that increased sleep will relieve symptoms and aid recovery. This idea commonly leads to frequent daytime naps and a delayed sleep-wake cycle.

Prospects for cure

There has been recent contention about the possibility of cure after graded exercise and cognitive behavioural therapy. An analysis of the PACE trial suggested cure was possible, but recovery outcomes were defined post hoc using population norms with generous thresholds (such as the population mean plus one standard deviation for self reported fatigue).15 This analysis was criticised because of the limited assessments and less than full restoration of health,16 leading to a recommendation that trials use more accurate outcomes (such as clinically relevant improvement) defined in advance and capturing a broad based return to health with assessments of fatigue and function.

Trialists must also consider patients’ perceptions of their
recovery.17 In this context, the increase in volume of grey matter
associated with clinical response to cognitive behavioural therapy, as reported in one study, needs further investigation.18 Even with the unduly liberal designation of recovery, less than one quarter of patients “recovered” in the PACE trial.

Even with the unduly liberal designation of recovery, less than one quarter of patients “recovered” in the PACE trial.

What then of the long awaited breakthrough? As is often the case in medical research, progress is predominantly made in modest increments not breakthroughs. The evidence for graded exercise and cognitive behavioural therapy is already clear, so this treatment should be made widely available. The next increments are to find ways to increase the symptom relief and functional improvement achieved by these treatments and to identify factors predicting clinically relevant improvement and non-response in order to increase the proportion of patients who benefit.

Notes
Cite this as: BMJ 2015;350:h2087

Footnotes
Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Doesn't strike me as too unreasonable as a summary of the status quo despite the fact that PACE demonstrated nothing.

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An uneducated person* could come away from it thinking nothing of significance has ever been found in biomedical research and that CBT and GET have been proven to be very helpful (though the recovery definition used was lax).

Interesting that this was commissioned and not peer reviewed. Which is presumably why the article does not appear to have anything very specific to say. In view of events elsewhere it seems a bit of a damp squib.

An uneducated person could come away from it thinking nothing of significance has ever been found in biomedical research and that CBT and GET have been proven to be very helpful (though the recovery definition used was lax).

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Frankly there's nothing off about stating that there have been no 'breakthroughs' in terms of finding a replicable and specific physiological abnormality in ME/CFS patients otherwise we wouldn't keep going on about the need to find a 'biomarker'.

Their suggestion that the primary abnormality lies in the central nervous system is very much in line with current findings and thinking and that the CNS be responding abnormally to normal physiological signals is exactly what researchers like Jared Younger are proposing (leptin levels correlating with fatigue were within normal physiological levels).

As for pre-existing mood disorders I doubt that there's sufficient evidence to support this but it wouldn't be surprising as 'mood' symptoms often predate obvious physical symptoms in various neurological diseases (which is after all what ME implies?).

The main issue where I would disagree with them is in their belief that PACE proved effectiveness but their theories aren't unreasonable and they seem to have at least ditched the simplistic notion of deconditioning. Graded exercise (mild as per PACE) as a means to desensitising central (microglial?) overreaction to physiological/metabolic signals is at least a (physical) theory and if we believe (as repeated studies show) that there is autonomic nervous system dysfunction with 'sympathetic dominance' then perhaps theoretically something like CBT may reduce that. If I were to suggest such a scenario and that something like mindfulness meditation might help then I doubt many would bat an eyelid. It would be somewhat hypocritical to deny any potential usefulness for CBT v mindfulness meditation just because of the messenger.

I could be wrong but I sense some movement here not least in the acknowledgement of the loose definition of 'recovery' and the acceptance that any improvement (in their view) due to GET/CBT was inadequate.

Coming up with fancy explanations for why CBT and GET might work when in fact they don't appear to work in terms of objective measures (subjective measures may simply represent response biases) doesn't impress or excite me. It's another way to continue prescribing ineffective therapies.

There hasn’t been much good news for patients with the prevalent but enigmatic disorder chronic fatigue syndrome (also referred to as myalgic encephalomyelitis). Over decades, research into the pathophysiology has failed to find convincing evidence of either persistent infection or immunological, endocrine, or metabolic change, and has rejected simplistic notions of depression (typical or atypical) or primary sleep disorder. Several notable “breakthroughs” have failed independent replication.

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my emphasis

This joker can't read or is living in a cave. Send him copy of IOM and Lipkin and Montoya studies.

Coming up with fancy explanations for why CBT and GET might work when in fact they don't appear to work in terms of objective measures (subjective measures may simply represent response biases) doesn't impress or excite me. It's another way to continue prescribing ineffective therapies.

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Well I'm neither impressed nor excited and I agree (as I said) that PACE proved nothing but I suspect a subtle crumbling of the deconditioning/false illness beliefs dogma that opens up the debate to physiological/neurological explanations.

The next increments are to find ways to increase the symptom relief and functional improvement achieved by these treatments and to identify factors predicting clinically relevant improvement and non-response in order to increase the proportion of patients who benefit.

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So there's no need to find the cause, treatment, or prevention of the illness. We just need better CBT and more therapists to tell patients that they're thinking the wrong thoughts.

I guess this is Sir Simon's answer to the Open Medicine Foundation's program of actual research.

This is not science but religion. Loyd and vd Meer are extremists in proclaiming CBT and GET. This stems from the fact that these professors have sought their lives for an explanation for this disease. Their vanity reveals their stupidity on the day there is a real breakthrough. At that point everybody can read there sloppy science and they will revealed as clowns.